Tissue factor (TF) is a cell membrane-bound glycoprotein (MW 46 kDa) and a member of the class 2 cytokine receptor family. It is composed of a hydrophilic extracellular domain, a membrane-spanning hydrophobic domain, and a cytoplasmic tail of 21 residues, including a non-disulfide-linked cysteine. The mature protein, which is post-translationally modified to include carbohydrate moieties, is biologically active. Upon exposure to blood, perivascular cell-bound TF binds to factor VII, a vitamin K-dependent serine protease unique among coagulation factor zymogens in that it exists in a partially active state. Cleavage of factor VII to VIIa by thrombin, factor IXa, Xa, or XIIa increases its activity 100-fold. The affinity of TF for factor VIIa is increased by anionic phospholipids. The TF-factor VIIa complex can directly or indirectly activate factor X and thence generate thrombin.
Under physiological conditions TF is expressed by cells not in contact with blood such as vascular smooth muscle, mesenchymal and epithelial cells including placental villous stromal cells. However, TF is not normally expressed by cells in contact with the circulation (i.e., endothelium and villous trophoblasts). Indeed, the pathological induction of TF expression in the endothelium contributes to the intravascular thrombosis of atherosclerosis and septic shock. Due to their perivascular location, enhanced TF expression by human endometrial DCs provides a mechanism to prevent hemorrhage during trophoblast invasion of the endometrial vasculature. Tissue factor expression is controlled at the transcriptional level in various cell types. Cytokines, growth factors, and serum transiently (1-4 hours) induce TF mRNA and protein in cultured cells from diverse tissues.
Tissue Factor/Factor VIIa Mediate Angiogenesis.
In addition to hemostasis, TF is now known to mediate invasion and angiogenesis. These functions apparently require interaction with factor VIIa. Embryonic lethal TF knock-out mice die in utero as a result of hemorrhage and the development of abnormally fragile vessels due to absence of normal vascular smooth muscle development. Whether these effects involve interactions of TF with factor VIIa is unclear. However, TF-factor VIIa interactions promote de novo synthesis and secretion of the potent angiogenic agent VEGF in lung fibroblasts. Current studies in our laboratory have shown that factor VIIa induces VEGF expression in cultured human endometrial stromal cells and that treatment of these cells with VIIa induces the stress activated kinases and their intermediates. We propose that abnormal angiogenesis associated with endometrial pathologies including breakthrough bleeding following progestin only contraception, myomas, polyps and malignancies are associated with aberrant expression of TF.